Genetic data to date indicate significant association with four risk genes for schizophrenia, even with this limited sample size. Ongoing whole genomic screening studies show evidence for increased (40%) rate for cytogenetic abnormalities and/or rare copy number variants (CNVs) that interrupt genes. This high rate of chromosome abnormalities may be related to early age of onset and to early developmental brain abnormalities rather than to schizophrenia. Skin biopsies are being obtained over the next three years on all childhood schizophrenia subjects for transformation to pluripotent stem cells for further physiological study in a collaborative study with Dr. Ricardo Dolmetsch (Stanford University). All known genes are being sequenced in a collaborative study with Dr. Guy Rouleau, University of Montreal. Children and adolescents meeting DSM-IV criteria for schizophrenia are being obtained through vigorous national recruiting for a study of the phenomenology, neurobiology and pharmacologic response of childhood onset schizophrenia. Over 3000 medical records have been reviewed from which 320 patients and their families appearing to meet DSM-IV criteria for schizophrenia with onset of psychosis prior to age 12, were screened in person. Of these 225 were hospitalized for medication free observation. A total of 112 received the diagnosis of schizophrenia at NIMH screening. A large number of children are receiving the diagnosis of schizophrenia inappropriately resulting in inappropriate treatment, even at academic centers. Our findings to date indicate continuity between childhood onset and later onset schizophrenia, with evidence that childhood onset schizophrenia may result from a more severe neurodevelopment lesion. Family/genetic data indicate three cases (5%) have familial schizophrenia, not higher than seen with adult cases;one subject had a 1:7 balanced chromosomal translocation;four subjects had a microdeletion at 22q11;one had uniparental isodisomy at 5q;two had 45x0 (Turners Syndrome);one had trisomy X. Three of 45 full siblings are mentally retarded with two of these meeting criteria for autism. Probands show greater premorbid developmental delays for motor skills and language development, than seen for the later onset disorder. Autonomic and eye tracking measures parallel these of adult schizophrenia. Brain MRI abnormalities ultimately resemble those of adult onset schizophrenia but with more striking and consistent progression during adolescence. This progressive loss appears specific to schizophrenia and not due to medication. A double-blind comparison of olanzapine and clozapine show superiority of clozapine for these medications for non-responders. Several lines of evidence indicate greater genetic loading for these cases and our national case finding is being expanded to obtain 120 probands for ongoing genetic studies (including complete parent-child trios).